Depression and anxiety impact the lives of millions and represent the leading causes of disability in the U.S among those aged 15-44. While more people are seeking treatment, clinical resources are struggling to keep up with demand, and not all who struggle with depression and anxiety respond to traditional therapeutic approaches. A new approach of at-home ketamine-assisted therapy (KAT) may offer a promising solution. By combining ketamine treatment with remote monitoring through telehealth platforms, KAT not only aims to address the lack of treatment options for depression and anxiety, but also tackle barriers to care access such as physician shortages and high cost of care. A recent trial by Hull et al. thus sought to assess the efficacy of KAT in treating these diseases, but noteworthy study flaws highlight the need for additional research.
Ketamine, an N-methyl-d-aspartate receptor antagonist and modulator of glutamatergic signaling, is a powerful medication which has long been used in medical settings for short-term pain management and as an anesthetic. It is used recreationally as an (illicit) hallucinogen due to its ability to induce a dissociative state, in which individuals feel detached from their bodies and surroundings, but at lower doses, ketamine’s effects on glutamatergic signaling in the brain may also make it an effective treatment for depression, anxiety, substance use disorders, and other psychiatric ailments. As Dr. Celia Morgan has explained on the podcast, several studies have indeed demonstrated ketamine’s efficacy in these therapeutic contexts.
Advantages of At-Home Treatments
Most previous studies on ketamine as a treatment for anxiety and depression have involved intravenous or intramuscular administration, both of which must be performed by a trained medical professional. Medical office visits are often costly and present a barrier for many seeking treatment, so attention is increasingly shifting toward at-home treatments that patients can perform themselves. One such option is to introduce ketamine sublingually, in which a ketamine tablet or troche is placed under the tongue and allowed to dissolve without swallowing, resulting in greater absorption and bioavailability than oral administration via swallowing.
Even at-home treatment with ketamine should be conducted only under professional guidance and direction, in part because ketamine carries a risk for addiction. Complementary psychotherapy is also a key part of effective therapeutic ketamine protocols for depression treatment. While prior approaches have involved a licensed behavioral health provider delivering on-site psychotherapy during and in conjunction with medication sessions, the rise of telemedicine has made it possible for patients to undergo psychotherapy remotely, reducing costs in time and money. Hence, KAT has been developed as a fully at-home treatment, utilizing low doses of sublingual ketamine in combination with traditional talk therapy via telemedicine.
About the Study
Hull et al. conducted a large, prospective study on the real-world safety and effectiveness of KAT for depression and anxiety. The study included 1247 patients with moderately-severe depression and/or severe anxiety at baseline, as defined by scores of ≥10 on the Patient Health Questionnaire 9 (PHQ-9) and/or the Generalized Anxiety Disorder scale (GAD-7) for depression and anxiety, respectively. Patients were otherwise free of serious illness, but of note, the use of other antidepressant or anxiolytic medications was not a criterion for exclusion, and the authors do not report the proportion of study participants who may have been taking such alternatives during the course of KAT treatment.
Patients received once-weekly KAT through a telehealth provider over a four-week period, for a total of four sessions. Ketamine was provided as sublingual tablets along with instructions, and behavioral guides met with patients prior to the first medication session to confirm the presence of a trusted friend or family member, to whom the guides provided training in patient support. After the medication session, patients would lie down, put on a study-supplied eye mask and headphones, and listen to music provided. After an hour, patients would journal for 30 minutes, followed by a 30-minute video meeting with their guide. Depression and anxiety symptoms were assessed using the PHQ-9 and GAD-7 at baseline, after the second KAT session, and after the fourth KAT session. Efficacy was determined as improvement in PHQ-9 or GAD-7 relative to baseline; no placebo or traditional therapy groups were included as controls.
The authors found that KAT was effective in improving symptoms of depression and anxiety in patients. Of the 1247 patients who completed at least two KAT sessions and the Week 2 assessment, 45.7% reported at least a 50% improvement in PHQ-9 score and 50.9% reported at least a 50% improvement in GAD-7 score. Of the 708 patients who completed all four KAT sessions, 62.8% reported a 50% or greater improvement on the PHQ-9 and 62.9% on the GAD-7 at the Week 4 assessment. Additionally, 32.6% reported a complete recovery from depression and 31.3% reported complete recovery from anxiety by the final assessment at Week 4. Average PHQ-9 scores improved from 15.3 (SD=3.9) at baseline to 7.3 (SD=4.8) after four KAT sessions, (95% CI: 1.48-1.73). Average GAD-7 scores improved from 14.8 (SD=3.3) at baseline to 7.1 (SD=4.6), (95% CI: 1.43-1.69).
Only a small percentage of patients experienced a worsening of symptoms for depression (0.9%) and anxiety (0.6%), and few patients left treatment early due to side effects or adverse events, none of which included addiction. These results suggest that at-home KAT has rapid and significant antidepressant and anxiolytic effects, similar to those seen in other forms of ketamine treatment, while adverse events were minimal.
One major limitation of this study is that half of the participants did not provide follow-up data and were therefore not included in the analysis. Namely, of 2,820 subjects included in safety analyses, only 1,247 provided follow-up data on symptom outcomes, and only 708 completed all four treatment sessions and both follow-up assessments. This means that the results – which were reported as percentages of the per protocol group – may not be representative of the entire original study population because the group of participants who provided follow-up data may be different in important ways from those who did not. (Per protocol analysis informs about efficacy–how something works if you do it exactly as prescribed; Intention-to-treat, ITT, analysis informs about effectiveness–how something works, period, even if you don’t fully follow through. In a good study, both per protocol and ITT analyses should be done.) For example, those who provided follow-up data may be more or less motivated, more or less healthy, or more or less compliant with the study protocol. As a result, the study findings may not generalize to the entire population of interest, complicating the task of drawing accurate conclusions or making reliable predictions based on the results.
Additionally, although the participants were generally classified in the moderately-severe category for depression and severe category for anxiety at baseline, they had relatively low baseline scores for depression and anxiety compared to other ketamine laboratory studies. This may have influenced the high rates of response and remission observed in the study, as low baseline scores make it more likely that individuals can meet the criteria for response and remission with relatively small improvements. Results of the study may therefore not be representative of what would happen in a population with higher baseline scores.
Ultimately, by far the biggest limitation of this study is that it does not have a control group. In any study measuring clinical outcomes, a control group – either using placebo or an established, alternative treatment – is critical in order to evaluate the true efficacy of the experimental intervention. Without any group for comparison, it is difficult to conclude anything about the effectiveness of the treatment being studied. Observed benefits may be due to other factors, such as a placebo effect or simply the natural course of a disease, rather than the treatment itself. Comparing the before-and-after results in a single set of test subjects, as was the case in this study, is prone to bias and confounding, whereas the presence of a control group allows researchers to control for these extraneous variables and make more accurate conclusions about the treatment being studied.
Where does KAT fit among options for treating depression?
KAT and ketamine are typically reserved for cases of treatment-resistant depression and anxiety, such as those that fail to improve after treatment with selective serotonin reuptake inhibitors (SSRIs). Hull et al. did not require participants to have a history of failed depression treatments, and it’s worth noting that their results may have changed had they exclusively studied a treatment-resistant population. Overall response rates are likely to have been lower, but alternative treatments for such cases are currently very limited – for instance, electroconvulsive therapy is a more invasive procedure which requires complete sedation and involves long recovery periods, raising the risk of serious side effects such as memory loss. So even if true KAT response rates are more modest than reported in Hull et al, the treatment might still be a promising addition to the short list of options for patients with treatment-resistant depression.
Ultimately, the power of ketamine may not be in the form of a standalone treatment, but rather a promising adjunctive therapy for treatment-resistant depression and anxiety. In fact, the nasal spray form of ketamine, esketamine, is only approved for use by the Food and Drug Administration when accompanied by SSRIs. In such situations, addition of ketamine may provide more rapid relief from depression symptoms. While most SSRIs can take weeks to take effect, a study by Zarate et al. found that ketamine can provide significant symptom improvement within just a few hours with relatively few side effects.
There is no one-size-fits-all solution for the treatment of depression and anxiety. It is important to carefully consider all treatment options and work with a healthcare provider to determine the best course of action that caters to individual needs and goals.
Hull and colleagues’ investigation opens the door to the possibility of at-home KAT as a viable and accessible solution for those with treatment-resistant anxiety and depression. Though initial findings suggest that this treatment approach may be safe, results of more robust studies – particularly randomized controlled trials – will be crucial for making any definitive conclusions about the true efficacy of KAT. Still, there exists a clear need for effective and convenient treatments for such mental health conditions, certainly justifying further exploration of the potential of at-home KAT.
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